Inosine monophosphate dehydrogenase (IMPDH) has been shown to be a key enzyme in the regulation of cell proliferation and differentiation. IMPDH is involved in the de novo synthesis of guanosine nucleotides, which are required for cells to divide and replicate. Because B and T lymphocytes depend on the de novo pathway, inhibitors of IMPDH have been shown to possess immunosuppressive activities, as well as antineoplastic, antiviral, and antiparasitic activities. IMPDH inhibitors have been proven advantageous in mammals—e.g. the prodrug of MPA (CellCept®) and other IMPDH inhibitors are useful drugs for treating transplant rejection and autoimmune disorders, including HIV. Various other IMPDH inhibitors are in clinical studies, including Vertex compound (VX-497), and/or have been approved for use in humans. See, e.g., Compilation, Current Medicinal Chemistry, Vol. 6, No. 7 (July 1999), Contents: Inhibition of Inosine Monophosphate Dehydrogenase (IMPDH), at 519 (“Over 300 literature citations now address the characterization, mechanism, and biological functions of IMPDH, its role as a target for both antileukemic and immunosuppressive therapy, and its inhibition by chemotherapeutic agents.”)
As may be appreciated, those in the field of pharmaceutical research continue to seek to develop new compounds and compositions having increased effectiveness and bioavailability and/or having fewer side effects. There is particularly an interest in developing agents that can selectively and directly inhibit key enzymes having significant biolological effects such as IMPDH. The present invention provides 2-substituted-5-oxazolyl indole compounds useful as inhibitors of IMPDH. Various aryl or heteroaryl substituted indole compounds useful for other purposes are disclosed in: WO 00/04013, WO 98/55123 and U.S. Pat. No. 5,780,437 to Merck & Co; European Pat. Applic. 581538 to Marck Sharp & Dohme Ltd; Goyal et al., “Electrochemical Oxidation of 4-Hydroxyindole and Effects of Its Oxidation Products on Blood Parameters of Albino Mice,” Bioorg. Chem., Vol. 27 (3) (1999), at pp. 239-252; Hiremath et al., “Synthesis of Substituted 2,5-Bis(Oxadiazolyl/Thiazolidino/Pyrazolyl/Pyrimidinediono)Indoles and Oxadiazolyl/Thiadiazolyl/Triazolyl/Thiazolidinone Analogs of Benzothiophene and their Antibacterial Activity,” Indian J. Heterocycl. Chem., Vol. 1(4) (1992) at pp. 177-84; and Hiremath et al., “Synthesis of Substituted 2,5-Bis(1,3,4-Oxadiazolyl/Thiazolidino/1,2,4-Triazolyl)Indoles and Study of their Biological Properties,” Indian J. Chem., Section B, Vol. 29B(12) (1990) at pp. 1118-24.